1,5- and 3-O-substituted 1H-indazoles having anti-asthmatic, anti-allergic, anti-inflammatory, immunomodulating and neuroprotective action, process for their preparation and their use as medicaments

ABSTRACT

The invention relates to 1,5- and 3-O-substituted 1H-indazoles of formula (I)

TECHNICAL FIELD

The invention relates to the preparation and use of novel derivatives ofindazol-3-ol as medicaments having anti-asthmatic, anti-allergic,anti-inflammatory, immuno-nodulating and neuroprotective properties.

PRIOR ART

Cyclosporin A (CsA) or FK 506 are immunosuppressant natural substancesoriginating from fungi, which inhibit the Ca²⁺ -dependent signaltransmission pathway in some cell types. In T cells, both compoundsinhibit the transcription of a number of genes. CsA and FK506 both bindwith high affinity to soluble receptor proteins such as, for example,cyclophilin (Cyp) or Ft-506 binding protein (FKBP) (G. Fischer et al.,Nature 337 (1989), 476-478; MW. Harding et al., Nature 341 (1989),755-760). Both proteins catalyse the isomerization of cis- andtrans-amide bond rotamases of eptides and are also often designated asmunophilins.

The complex of CsA-Cyp or FR 506-FKBP binds calcineurin (CN) andinhibits its phosphatase activity. The cytosolic, phosphorylatingcomponent of the transcription factor NF-AT was recognized as a cellulartarget molecule of CN, so that in the absence of CN activity the activetranscription complex on the IL 2 promoter cannot be switched on (M. K.Rosen, S. L. Schreiber, Angew. Chem. 104 (1992), 413-430; G. Fischer,Angew. Chem. 106 (1994), 1479-1501).

The allergic, asthmatic diseases are based on an inflammatory reactionwhich is controlled by T cells and their mediators. Corticosteroids arestill the agent of choice in the treatment of many allergic diseases.CsA and FK 506 also proved to be a favourable therapeutic in bronchialasthma and underlying inflammations both in animal experiments and inclinical studies.

Despite the large number of attempts at the identification of new activeimmunophilin inhibitors, until now it was not possible to prepare orisolate any more active structures than CsA, FK 506, rapamycin orderivatives of these natural substances. The high inhibitory potentialof CsA, FK 506 and rapamycin, however, is very considerably reduced bythe various side effects, in particular the renal toxicity andneurotoxicity (N. H. Sigal et al., J. Exp. Med. 173 (1991), 619-6128).What is behind this fact is the non-specificity of the interactionbetween immunophilin ligands and the cell-specific binding proteins. Asa result, the known medicinal-therapeutic action of theseimmunosuppressants is considerably restricted. Furthermore, the lackingselectivity of the compounds proves to be problematic especially inlong-term therapy.

Substances which inhibit the activity of peptidylprolyl isomerases(PPIases) such as Cyp or FKBF, have neuroprotective properties,stimulate neuronal growth and are suitable for the treatment ofneurodegenerative diseases (WO 96/40140, U.S. Pat. No. 5,696,135, WO97/18828).

Substituted indazole derivatives are known which, however, differ fromthe claimed compounds with respect to the substituents X, Y, Z, R¹, R²and R³ and their pharmacodynamic action.

Corsi [Boll. Chim. Farm. 111, 566-572 (1972)] and Giannangeli et al.[Boll. Chim. Farm. 121, 465-474 (1982)] reported on the synthesis of5-hydroxybendazac and EP-A-0 191 520 describes the use of (1-benzyl-5hydroxy-1H-indazol-3-yl)acetic acid for the treatment of colds.

Baiocchi et al. [Synthesis 1978 (9), 633-648] give a general survey ofsyntheses and properties of the 1H-indazol-3-ols.

WO 97/34874 describes 1,3,5-trisubstituted indazoles havinganti-asthmatic, anti-allergic, anti-inflammatory and immunomodulatingaction.

WO 96/04266 includes, inter alia, (1H-indazol-3-yloxy)-acetamidessubstituted by basic radicals and their anti-asthmatic, anti-allergic,anti-inflammatory and immunomodulating properties.

Pfannstiel et al. [Ber. Dtsch. Chem. Ges. 75 (9), 1096-1107 (1942)]reported on the preparation of nitro-1H-indazol-3-ols.

Ketami et al. [J. Heterocycl. Chem. 7 (4), 807-813 (1970)] describe theanti-inflammatory action of the 1,5-disubstituted3-hydroxy-1H-indazoles.

Hannig et al. [Pharmazie, 30 (11), 706-708] describe 1-benzylated(indazol-3-yl)acylaminocarboxanilides.

JP 48026760 includes, inter alia, 1-benzyl-1H-indazol-3-yloxyacetamides.

EP-A-0 290 145 comprises 1,3,6-trisubstituted indazoles, which areleukotriene antagonists.

U.S. Pat. No. 3,470,194, Pallazo et al. [J. Med. Chem. 9, 38-41 (1966)]and Guyla et al. [Acta pharm. Hung. 44, 49-57 (1974)] describe1,5-disubstituted (indazol-3-yl)oxy-alkanoic acids and theiranti-inflammatory activity.

Klicnar [Coll. Czech. Chem. Comm. 42, 327-337 (1977)] reports onphysical data of the acylindazoles.

Yamaguchi et al. [Chem. Pharm. Bull. 43 (2), 332-334 (1995)] describes3-O-substituted (1-pyridin-3-yl)-indazoles and their anti-asthmaticaction.

EP 0 448 206 comprises 1,3,6-trisubstituted indazoles and their use asherbicides, only OH or O-alkyl being permitted in the 3-position.

EP 0 191 520 describes(1-phenylmethyl)-5-hydroxy-1H-indazol-3-yl)oxyacetic acid and itspharmaceutical use.

EP 0 199 543 describes indazoles and other heterocycles having acidicsubstituents in the radical M as leukotriene antagonists.

U.S. Pat. No. 3,966,761 includes trisubstituted aminoindazoles and theiranti-inflammatory and analgesic effects.

U.S. Pat. No. 3,318,905 describes 3-dialkylaminoalkyloxyindazoles havinganalgesic and anti-inflammatory activity.

K. v. Auwers [Ber. Dtsch. Chem. Ges. 58, 2081-2088 (1925)] describes theconstitution of acylindazoles.

Zoni et al. [Il Farmaco Ed. Sci. 23 (5), 490-501 (1968)] and Zoni et al.[Boll. Chim. Farm. 107, 598-605 (1968)] describe the alkylation of1-substituted 1H-indazol-3-ols.

Evans et al. [Tetrahedron 21, 3351-3361 (1965)] describe the synthesisof 1,3-substituted acyl- and tosylindazoles.

Anderson et al. [J. Chem. Soc. C, 3313-3314 (1971)] describe1,3-substituted tosylindazoles.

Schmutz et al. [Helv. Chim. Acta 47, 1986-1996 (1964)] describe thealkylation of indazolones.

On account of numerous side effects of the preparations introduced, lackof curative effects and the hitherto too non-specific therapy, a greatneed for compounds having a high effectiveness and safety furthermoreexists for the treatment of asthmatic diseases.

The invention is based on the object of finding new compounds havingrotamase-inhibiting and/or pulmonary eosinophil infiltration-inhibitingproperties and making them available by targeted synthesis. A completelynovel class of substance, which surprisingly binds immunophilinsspecifically, is represented by the compounds of the formula I accordingto the invention. This class of compounds has a high affinity forimmunophilins such as CypB.

DESCRIPTION OF THE INVENTION

Surprisingly, it has now been found that the new indazole derivativesare able to inhibit the action of PPIase. Accordingly, these compoundsare of great importance for the production of medicaments where theinhibition of PPIase is of benefit. Such illnesses are, for example:peripheral neuropathies, neuro-degeneration, stroke, Parkinson's andAlzheimer's diseases, traumatic brain diseases, multiple sclerosis. Ithas furthermore been demonstrated that the compounds according to theinvention are able to inhibit the infiltration of eosinophilicgranulocytes into the tissue, which is characteristic of the asthmaticlate-phase reaction.

The invention relates to new 1,5- and 3-O-substituted 1H-indazoles ofthe general formula I ##STR2## in which X, Y, Z, R¹, R² and R³ have thefollowing meaning: X can be --SO₂ --, --SO--, --(CH₂)_(p) --,--(CH₂)_(p) --O--, --(CH₂)_(p) --(C═O)--, --(CH₂)_(p) --(C═O)--NH--,--(CH₂)_(p) --CHOH--, --CHOH--(CH₂)_(p) --, --(CH₂)_(p) --CH═CH--,--CH═CH--(CH₂)_(p) -- where p=1 . . . 4,

Y can be --(CH₂)_(p) --, --(CH₂)_(p) --O--, --(CH₂)_(p) --(C═O)--,--(CH₂)_(p) --(C═O)--NH--, --(CH2)_(p) --(C═O)--NH--(CH₂)_(p) --,--(CH₂)_(p) --CHOH--, --CHOH--(CH₂)_(p) --, --(CH₂)_(p) --CH═CH--,--CH═CH--(CH₂)_(p) -- where p=1 . . . 4,

Z can be --O--, --S--, --SO--, --SO₂ --, --O--(CH₂).sub. p-- where p=1 .. . 4, --NH--, --NH--(C═O)--, --NH--(C═O)--NH--, --NH--(C═O)--O--,--NH--CH₂ --(C═O)-- and --NH--(C═O)--CH₂ --,

R¹, R² and R³ can be identical or different and have the followingmeaning:

mono-, bi- or tricyclic saturated or mono- or polyunsaturatedcarbocycles having 5 . . . 14 ring members, in particular phenyl,naphthyl, anthranyl, fluorenyl; or mono-, bi- or tricyclic saturated ormono- or polyunsaturated heterocycles having 5 . . . 15 ring members and1 . . . 6 heteroatoms, which are preferably N, O and S, in particularthiophenyl, pyridinyl, isoxazolyl, benzimidazolyl, benzo[1,3]dioxolyl,pyrimidinyl, quinolyl, quinazolinyl, morpholinyl, pyrrolidinyl,pyrrolyl, benz[1,2,4]oxadiazolyl, benzothiazolyl, where the carbocyclesand the heterocycles can be mono- or polysubstituted by:

--C₁ . . . 6 -alkyl, --O--C₁ . . . 6 -alkyl, --O--C₃ . . . 7-cycloalkyl, mono-, bi- or tricyclic saturated or mono- orpolyunsaturated carbocycles having 3 . . . 14 ring members, mono-, bi-or tricyclic saturated or mono- or polyunsaturated heterocycles having 5. . . 15 ring members and 1 . . . 6 heteroatoms, which are preferably N,O and S, --F, --Cl, --Br, --I, --OH, --SH, --NO₂, --NH₂, --NHC₁ . . . 6-alkyl, --N(C₁ . . . 6 -alkyl)₂, --NHC₆ . . . 14 -aryl, --N(C₆ . . . 14-aryl)₂, --N(C₁ . . . 6 -alkyl)--(C₆ . . . 14 -aryl), --NHCOC₁ . . . 6-alkyl, --NHCOC₆ . . . 14 -aryl, --CONHC₁ . . . 6 -alkyl, --CONHC₆ . . .14 -aryl, --CONHSO₂ C₁ . . . 6 -alkyl, --CONHSO₂ C₆ . . . 14 -aryl,--CN, --(CO)C₁ . . . 6 -alkyl, --(CS)C₁ . . . 6 -alkyl, --COOH, --COOC₁. . . 6 -alkyl, --O--C₆ . . . 14 -aryl, --O--(CO)C₁ . . . 6 -alkyl,--O--(CO)C₆ . . . 14 -aryl, benzyl, benzyloxy, --S--C₁ . . . 6 -alkyl,--S--C₆ . . . 14 -aryl, --CF₃, --(CH₂)_(p) --COOH where p=1 to 4,--(CH₂)_(p) --COOC₁ . . . 6 -alkyl where p=1 to 4, --SO₂ --C₁ . . . 6-alkyl, --SO₂ --C₆ . . . 14 -aryl,

R¹ can furthermore be H (but not if X=CH₂),

R³ --Z can furthermore be NO₂.

The compounds according to the invention are new, but excludingcompounds as in formula I:

if Y=--(CH₂)_(p) --(C═O)--, --(CH₂)_(p) --(C═O)--NH-- where p=1 . . . 4,then R² must not be pyridine, piperazine, pyrimidine,tetrahydropyridine;

if z is --NH--(C═O)--, --NH--(C═O) --NH--, --NH--(C═O)--O--,--NH--(C═O)--CH₂ -- and simultaneously R¹ =phenyl, monosubstituted orpolysubstituted by --COOH, --COOC₁ . . . 6 -alkyl, --(CH₂)_(p) --COOH,where p=1 to 4, --(CH₂)_(p) --COOC₁ . . . 6 -alkyl where p=1 . . . 4,--CONHC₁ . . . 6 -alkyl, --CONHC₆ . . . 14 -aryl, --CONHSO₂ C₁ . . . 6-alkyl, --CONHSO₂ C₆ . . . 14 -aryl, 1H-tetra-zol-5-yl, then R² must notbe phenyl, monosubstituted or polysubstituted by CN, halogen, C₁ . . . 4-alkyl, C₁ . . . 4 -alkyloxy, CF₃ ;

if R³ --Z=NO₂, then R¹ --X and R² --Y must not simultaneously have thefollowing meaning:

R¹ --X=benzyl, 4-methoxybenzyl

R² --Y=benzyl, 2-picolyl.

The invention furthermore relates to the physiologically tolerable saltsof the compounds according to formula I. The pharmacologically tolerablesalts are obtained in a customary manner by neutralization of the baseswith inorganic or organic acids or by neutralization of the acids withinorganic or organic bases. Possible inorganic acids are, for example,hydrochloric acid, sulphuric acid, phosphoric acid or hydrobromic acid,organic acids are, for example, carboxylic, sulpho or sulphonic acidssuch as acetic acid, tartaric acid, lactic acid, propionic acid,glycolic acid, malonic acid, maleic acid, fumaric acid, tannic acid,succinic acid, alginic acid, benzoic acid, 2-phenoxybenzoic acid,2-acetoxybenzoic acid, cinnamic acid, mandelic acid, citric acid, malicacid, salicylic acid, 3-aminosalicylic acid, ascorbic acid, embonicacid, nicotinic acid, isonicotinic acid, oxalic acid, amino acids,methanesulphonic acid, ethanesulphonic acid, 2-hydroxyethanesulphonicacid, ethane-1,2-disulphonic acid, benzenesulphonic acid,4-methylbenzenesulphonic acid or naphthalene-2-sulphonic acid. Possibleinorganic bases are, for example, sodium hydroxide solution, potassiumhydroxide solution, ammonia and organic bases are amines, preferably,however, tertiary amines, such as trimethylamine, triethylamine,pyridine, N,N-dimethylaniline, quinoline, isoquinoline, α-picoline,β-picoline, γ-picoline, quinaldine or pyrimidine.

In addition, physiologically tolerable salts of the compounds accordingto formula I can be obtained by converting derivatives which havetertiary amino groups into the corresponding quaternary ammonium saltsin a manner known per se. Possible quaternizing agents are, for example,alkyl halides such as methyl iodide, ethyl bromide and n-propylchloride, but also arylalkyl halides such as benzyl chloride or2-phenylethyl bromide.

Furthermore, the invention of compounds of the formula I which containan asymmetric carbon atom relates to the D form, the L form and D,Lmixtures and, in the case of a number of asymmetric carbon atoms, thediastereomeric forms. Those compounds of the formula I which containasymmetric carbon atoms and are obtained as a rule as racemates, can beseparated into the optically active isomers in a manner known per se,for example using an optically active acid. However, it is also possibleto employ an optically active starting substance from the beginning, acorresponding optically active or diastereomeric compound then beingobtained as a final product.

The invention relates to the use of the compounds according to theinvention or their physiologically tolerable salts as

1. inhibitors of PPIase for the production of medicaments for thetreatment of diseases mediated by this enzyme and/or

2. inhibitors of late-phase eosinophilia for the production ofmedicaments for the treatment of diseases mediated by these cells.

These diseases include, for example, bronchial asthma, allergicrhinitis, allergic conjunctivitis, a topic dermatitis, eczema, allergicangiitis, inflammations mediated by eosinophils such as eosinophilicfasciitis, eosinophilic pneumonia and PIE syndrome, autoimmune diseasessuch as rheumatoid arthritis, rheumatoid spondylitis, lupuserythematosus, multiple sclerosis, psoriasis, glomerulonephritis anduveitis, insulin-dependent diabetes mellitus and sepsis. The compoundsaccording to the invention or their physiologically tolerable salts arefurthermore used for the production of medicaments for the prevention ofrejection reactions after transplantation of cells, tissues or organs.

For the production of the medicaments, in addition to the customaryauxiliaries, carriers and additives, an efficacious dose of thecompounds according to the invention or their salts is used. The dose ofthe active compounds can vary depending on the administration route,age, weight of the patient, nature and severity of the diseases to betreated and similar factors. The daily dose can be given as anindividual dose to be administered once or subdivided into two or moredaily doses and is, as a rule, 0.001-1000 mg.

Possible administration forms are oral, parenteral, intravenous,transdermal, topical, inhalational and intranasal preparations.

For administration, possible customary pharmaceutical preparation formsare those such as tablets, coated tablets, capsules, dispersiblepowders, granules, aqueous solutions, aqueous or oily suspensions,syrup, juices or drops.

Solid pharmaceutical forms can contain inert ingredients and carriers,such as, for example, calcium carbonate, calcium phosphate, sodiumphosphate, lactose, starch, mannitol, alginates, gelatin, guar gum,magnesium or aluminium stearate, methylcellulose, talc, highly dispersesilicic acids, silicone oil, high molecular weight fatty acids (such asstearic acid), gelatin, agar-agar or vegetable or animal fats and oils,solid high molecular weight polymers (such as polyethylene glycol);preparations suitable for oral administration can contain, if desired,additional flavourings and/or sweeteners.

Liquid pharmaceutical forms can be sterilized and/or optionally containauxiliaries such as preservatives, stabilizers, wetting agents,penetrating agents, emulsifiers, spreading agents, solubilizers, salts,sugars or sugar alcohols for regulating the osmotic pressure or forbuffering, and/or viscosity regulators. Additives of this type are, forexample, tartrate and citrate buffers, ethanol, complexing agents (suchas ethylenediaminetetraacetic acid and its non-toxic salts). Forregulating the viscosity, possible high molecular weight polymers arethose such as, for example, liquid polyethylene oxide, microcrystallinecelluloses, carboxymethylcelluloses, polyvinylpyrrolidones, dextrans orgelatin. Solid carriers are, for example, starch, lactose, mannitol,methylcellulose, talc, highly disperse silicic acids, high molecularweight fatty acids (such as stearic acid), gelatin, agar-agar, calciumphosphate, magnesium stearate, animal and vegetable fats, solid highmolecular weight polymers such as polyethylene glycol.

Oily suspensions for parenteral or topical application can be vegetablesynthetic or semi-synthetic oils such as, for example, liquid fatty acidesters in each case having 8 to 22 C atoms in the fatty acid chains, forexample palmitic, lauric, tridecylic, margaric, stearic, arachic,myristic, behenic, pentadecanoic, linoleic, elaidic, brassidic, erucicor oleic acid, which are esterified with mono- to trihydric alcoholshaving 1 to 6 C atoms, such as, for example, methanol, ethanol,propanol, butanol, pentanol or their isomers, glycol or glycerol. Fattyacid esters of this type are, for example, commercially availableMiglyols, isopropyl myristate, isopropyl palmitate, isopropyl stearate,PEG 6-capric acid, caprylic/capric acid esters of saturated fattyalcohols, polyoxyethylene glycerol trioleates, ethyl oleate, waxy fattyacid esters such as artificial duck preen gland fat, isopropyl cocoate,oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate,diisopropyl adipate, polyol fatty acid esters and others. Also suitableare silicone oils of differing viscosities or fatty alcohols such asisotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or oleylalcohol, fatty acids such as, for example, oleic acid. It is furthermorepossible to use vegetable oils such as castor oil, almond oil, oliveoil, sesame oil, cottonseed oil, groundnut oil or soya bean oil.

Possible solvents, gelling agents and solubilizers are water orwater-miscible solvents. Those suitable are, for example, alcohols suchas, for example, ethanol or isopropyl alcohol, benzyl alcohol,2-octyldodecanol, polyethylene glycols, phthalates, adipates, propyleneglycol, glycerol, di- or tripropylene glycol, waxes, methylcellosolve,cellosolve, esters, morpholines, dioxane, dimethyl sulphoxide,dimethylformamide, tetrahydrofuran, cyclohexanone etc.

Film-forming agents which can be used are cellulose ethers whichdissolve or swell both in water and in organic solvents, such as, forexample, hydroxypropylmethylcellulose, methylcellulose, ethylcelluloseor soluble starches.

Mixed forms between gel- and film-forming agents are also perfectlypossible. Here, especially, ionic macromolecules are used, such as, forexample, sodium carboxymethylcellulose, polyacrylic acid,polymethacrylic acid and its salts, sodium amylopectin semiglycolate,alginic acid or propylene glycol alginate as the sodium salt, gumarabic, xanthan gum, guar gum or carrageenan.

Further formulation auxiliaries which can be employed are: glycerol,paraffin of differing viscosities, triethanolamine, collagen, allantoin,novantisolic acid. The use of surfactants, emulsifiers or wetting agentscan also be necessary for formulation, such as, for example, of Nalaurylsulphate, fatty alcohol ether sulphates, di-NaN-lauryl-β-iminodipropionate, polyethoxylated castor oil or sorbitanmonooleate, sorbitan monostearate, polysorbates (e.g. Tween), cetylalcohol, lecithin, glycerol monostearate, polyoxyethylene stearate,alkylphenyl polyglycol ethers, cetyltrimethylammonium chloride ormono-/dialkyl polyglycol ether orthophosphoric acid monoethanolaminesalts. Stabilizers such as montmorillonites or colloidal silicic acidsfor the stabilization of emulsions or for the prevention of thebreakdown of the active substances, such as antioxidants, for exampletocopherols or butylhydroxyanisole, or preservatives, such asp-hydroxybenzoic acid esters, can also be necessary for the preparationof the desired formulations.

The preparation, dispensation and sealing of the preparations is carriedout under the customary antimicrobial and aseptic conditions.

The dose of the pharmaceutical preparations depends on the age,condition and weight of the patient and on the administration form. As arule, the daily dose of active compound is between 0.001 and 25 mg/kg ofbody weight.

Preparation

According to the present invention, the compounds of the general formulaI can be prepared by the following processes:

Process for the preparation of the compounds of the general formula I,according to claim 1, characterized in that

a) for X=--SO₂ --, --SO-- the reaction is carried out according toscheme 1.

1H-Indazol-3-yl sulphonates II are reacted in the presence of a baseand, if appropriate, in the presence of a diluent to give compounds ofthe general formula III, where R¹ ₁, R³, X and Z have the abovementionedmeaning. 1H-Indazol-3-yl sulphonates II or 1-sulphonylindazoles III arereacted, if appropriate in the presence of a base, in particular sodiumhydride, and if appropriate in the presence of a diluent, in particulardimethyl sulphoxide, with compounds of the general formula Hal-Y-R²where R¹, R², R³, X, Y and Z have the abovementioned meaning and Hal isa halogen atom F, Cl, Br or iodine, to give compounds of the generalformula I, where R¹, R², R³, X, Y and Z have the abovementioned meaning.

Scheme 1: ##STR3##

b) for X=--(CH₂)_(p) --, --(CH₂)_(p) --O--, --(CH₂)_(p) --(C═O)--,--(CH₂)_(p) --(C═O)--NH--, --(CH₂)_(p) --CHOH--, --CHOH--(CH₂)_(p) --,--(CH₂)_(p) --CH═CH--, --CH═CH--(CH₂)_(p) -- where p=1 . . . 4 thereaction is carried out according to scheme 2.

Compounds of the general formula III are reacted, if appropriate in thepresence of a base, in particular sodium hydride, and if appropriate inthe presence of a diluent, in particular dimethyl sulphoxide, withcompounds of the general formula Hal-Y-R² where R¹, R², R³, X, Y and Zhave the abovementioned meaning and Hal is a halogen atom F, Cl, Br oriodine, to give compounds of the general formula I, where R¹, R², R³, X,Y and Z have the abovementioned meaning.

Scheme 2: ##STR4## where formula III can also be present as thetautomeric form formula IV according to scheme 3.

Scheme 3: ##STR5##

The compounds of the general formula I are new.

WORKING EXAMPLES

The following representatives of the compounds according to theinvention are mentioned by way of example:

3-[2-(2-bromo-4,6-difluorophenoxy)ethoxy]-5-methoxy-1-(toluene-4-sulphonyl)-1H-indazole

5-methoxy-1-(toluene-4-sulphonyl)-3-[5-(3-trifluoromethylphenyl)-1,2,4-oxadiazol-3-ylmethoxy]-1H-indazole

6-{2-[5-methoxy-1-(toluene-4-sulphonyl)-1H-indazol-3-yloxy]acetyl}-3,4-dihydro-1H-quinolin-2-oneN-(2,4-difluorophenyl)-2-[5-methoxy-1-(toluene-4-sulphonyl)-1H-indazol-3-yloxy]acetamide

3-(6-chlorobenzo[1,3]dioxol-5-ylmethoxy)-5-methoxy-1-(3-nitrobenzyl)-1H-indazole

3-[3-(4-fluorophenyl)propoxy]-5-nitro-1-(3-nitrobenzyl)-1H-indazole

3-[3-(6-chlorobenzo[1,3]dioxol-5-ylmethoxy)-5-methoxyindazol-1-ylmethyl]phenylamine

1-(4-fluorobenzyl)-5-methoxy-3-[2-(4-nitrophenoxy)-ethoxy]-1H-indazole

3-[2-(2-bromo-4,6-difluorophenoxy)ethoxy]-5-methoxy-1-[2-(4-nitrophenoxy)ethyl]-1H-indazole

3-[2-(2-bromo-4,6-difluorophenoxy)ethoxy]-1-[3,4-dichlorobenzyl]-5-methylthio-1H-indazole

1-{1-(2,4-dichlorobenzyl)-3-[2-(4-nitrophenoxy)ethoxy]-1H-indazol-5-yl}-3-naphthalen-1-ylurea

The compounds are characterized by means of melting point, thin-layerchromatography, elemental analysis, NMR spectroscopy, IR and UV-VISspectroscopy and optionally using mass spectroscopy.

Purification using column liquid chromatography: In the preparation ofthe compounds of Examples 1 to 123, the 1,2-dihydroindazol-3-onesaccording to the general formula V can be formed as by-products.##STR6##

The compounds of the general formula I can usually be separated from thecompounds of the general formula V by recrystallization. If this isunsuccessful, a column-chromatographic separation under the followingconditions is necessary: stationary phase: normal phase silica gel, e.g.Si 60 to 100 Å, particle size 5 to 100 μM. Eluent: methylenechloride/ethyl acetate=95/5 or methylene chloride/methanol=95/5. Thecompounds of the general formula V are more polar than the compounds ofthe general formula I, so the compounds of the general formula I areeluted first under these chromatographic conditions. This purificationoperation is applicable to all of Examples 1 to 123.

EXAMPLE 13-[2-(2-Bromo-4,6-difluorophenoxy)ethoxy]-5-methoxy-1-(toluene-4-sulphonyl)-1H-indazole##STR7##

31.8 g (100 mmol) of 5-methoxy-1H-indazol-3-yl toluene-4-sulphonate aredissolved in 300 ml of DMSO and treated in portions with 3.54 g (140mmol) of sodium hydride (95 per cent). After stirring for 15 minutes, asolution of 28.5 g (105 mmol) of1-(2-bromo-4,6-difluorophenoxy)-2-chloroethane in 100 ml of DMSO isadded dropwise and the mixture is stirred at 90° C. for 3 hours. Aftercooling, it is stirred into 1.5 l of water, the mixture is extractedthree times with 400 ml of ethyl acetate each time, the organic phase isdried over sodium sulphate and distilled to dryness in vacuo, and theresidue is recrystallized from ethanol.

Yield: 25.1 g (45.3% of theory); m.p. 133-134.5° C.; ¹³ C-NMR (DMSO-d₆ ;300 MHz): δ=21.3 CH₃ ; 55.9 CH₃ O; 69.3 and 72.1 each CH₂ O.

The starting materials used for the preparation of Examples 2 to 76(Tables 1, 2, 3 and 4) were the following products:

5-methoxy-1H-indazol-3-yl toluene-4-sulphonate

5-methoxy-1H-indazol-3-yl 4-chlorobenzenesulphonate

5-methoxy-1H-indazol-3-yl 4-fluorobenzenesulphonate

5-methoxy-1H-indazol-3-yl 4-methoxybenzenesulphonate

5-methoxy-1H-indazol-3-yl 4-trifluoromethoxybenzenesulphonate

5-methoxy-1H-indazol-3-yl thiophene-2-sulphonate

5-methoxy-1H-indazol-3-yl 4-acetylaminobenzenesulphonate

5-methoxy-1H-indazol-3-yl quinoline-8-sulphonate

5-methoxy-1H-indazol-3-yl naphthalene-1-sulphonate

5-methoxy-1H-indazol-3-yl 2,5-dichlorobenzenesulphonate

4-(5-methoxy-1H-indazol-3-yloxysulphonyl)benzoic acid

5-nitro-1H-indazol-3-yl toluene-4-sulphonate

5-nitro-1H-indazol-3-yl 4-methoxybenzenesulphonate

The synthesis of the compounds of Examples 2 to 31 is carried outanalogously to the procedure according to Example 1. Further startingmaterials used are correspondingly R³ - and (CH₂)_(n) -substitutedphenoxyalkyl bromides or chlorides.

                                      TABLE 1                                     __________________________________________________________________________    3-Phenoxyalkyloxyindazole-1-sulphonamides                                                                        Formula VI                                 R.sup.1 = CH.sub.3 O                                                                                           .sup.13 C-NMR                                        (DMSO-d.sub.6)                                                              Yield M.p. CH.sub.2                                                       Example R.sup.2 R.sup.3 n (% of theory) [° C.] [ppm]                 __________________________________________________________________________     2   4-Tolyl                                                                             Phenyl                                                                             2 37       140   65.22; 68.26                                        (2-PrOH)                                                                  3 4-Tolyl Phenyl 3 29 113-115 28.51; 64.24;                                       (2-PrOH) 66.99                                                            4 4-Tolyl Phenyl 4 22 136-137 25.37; 25.60                                        (2-PrOH) 67.32; 69.75                                                     5 4-Tolyl 2-Bromo- 2  6 123-125 64.92; 66.24                                   phenyl   (MeOH)                                                              6 4-Tolyl 4-Chloro- 2 26 153 64.73; 67.13                                      phenyl   (2-PrOH)                                                            7 4-Chloro- 4-Chloro- 2  9 149-154 66.24; 68.74                               phenyl phenyl   (MeCN)                                                        8 4-Fluoro- 4-Chloro- 2 29 121-126 65.48; 67.97                               phenyl phenyl   (EtOH)                                                        9 4-Methoxy- 4-Chloro- 2 37 160-162 66.26; 68.61                              phenyl phenyl   (2-PrOH)                                                     10 4-Tri- 4-Chloro- 2 22 117-120 66.24; 68.77                                  fluoro- phenyl   (MeCN)                                                       methoxy-                                                                      phenyl                                                                       11 4-Tolyl 2,6-Di- 2 34 136-137.5 69.24; 71.42                                  chloro-   (MeCN)                                                              phenyl                                                                      12 4-Tolyl 2,4-Di- 2 15  96-100 67.87; 68.69                                    fluoro-   (EtOAc)                                                             phenyl                                                                      13 4-Tolyl 2,6-Di- 2 21 101-102.5 69.35; 72.20                                  fluoro-   (EtOH)                                                              phenyl                                                                      14 4-Tolyl 2,4,6- 2  7 110-111.5 69.29; 72.45                                   Tri-   (EtOH)                                                                 fluoro-                                                                       phenyl                                                                      15 4-Methoxy- 2-Bromo- 2 10 119-121.5 67.64; 70.49                             phenyl 4,6-di-   (EtOAc)                                                       fluoro-                                                                       phenyl                                                                      16 4-Chloro- 2-Bromo- 2  5 138-139.5 69.41; 72.05                              phenyl 4,6-di-   (EtOH)                                                        fluoro-                                                                       phenyl                                                                      17 4-Tolyl 2,6-Di- 2 16 131 69.17; 72.17                                        bromo-4-   (MeCN)                                                             nitro-                                                                        phenyl                                                                      18 4-Methoxy- 2,6-Di- 2 14 153 69.72; 72.73                                    phenyl bromo-4-   (EtOH)                                                       nitro-                                                                        phenyl                                                                      19 4-Tolyl 4-Nitro- 2  9 152-156 66.92; 68.40                                   phenyl   (2-PrOH)                                                           20 4-Chloro- 4-Nitro- 2 16 159-161 66.91; 68.49                                phenyl phenyl   (MeCN)                                                       21 4-Methoxy- 4-Nitro- 2 20 174-178 66.96; 68.37                               phenyl phenyl   (2-PrOH)                                                     22 2-Thio- 4-Nitro- 2 35 150-155 66.93; 69.58                                  phenyl phenyl   (MeOH)                                                       23 4-Tolyl 4-Cyano- 2 19 148-151 65.64; 67.65                                   phenyl   (2-PrOH)                                                           24 4-Tolyl 4-Carbox- 2 15 175-180 66.03; 68.62                                  amido-   (2-PrOH)                                                             phenyl                                                                    __________________________________________________________________________

Starting from 5-nitro-1H-indazol-3-yl toluene-4-sulphonate, thefollowing derivatives were prepared analogously:

    ______________________________________                                        Formula VI, R.sup.1 = NO.sub.2                                                                             Yield         .sup.13 C-NMR                        Ex-    (% of M.p. (DMSO-d.sub.6)                                              ample R.sup.2 R.sup.3 n theory) [° C.] CH.sub.2 [ppm]                ______________________________________                                        25    4-Tolyl 4-Chloro-                                                                              2   58    150     65.05;68.10                              phenyl   (MeCN)                                                             26 4-Tolyl 2,6-Di- 2 35 117-125 69.88;71.21                                     chloro-   (n-BuOH)                                                            phenyl                                                                      27 4-Tolyl 2,6-Di- 2 25 120 69.93;72.07                                         fluoro-   (n-BuOH)                                                            phenyl                                                                      28 4-Tolyl 2,6-Di- 2 48 159 69.88;72.14                                         bromo-4-   (n-BuOH)                                                           nitro-                                                                        phenyl                                                                      29 4-Tolyl 4-Nitro- 2 20 212-216 65.39;67.54                                    phenyl   (MeCN)                                                           ______________________________________                                    

By reduction of the 5-nitro group corresponding to the procedure as into Example 87, the following derivatives were prepared:

    ______________________________________                                        Formula VI, R.sup.1 = NH.sub.2                                                                             Yield         .sup.13 C-NMR                        Ex-    (% of M.p. (DMSO-d.sub.6)                                              ample R.sup.2 R.sup.3 n theory) [° C.] CH.sub.2 [ppm]                ______________________________________                                        30    4-Tolyl 4-Chloro-                                                                              2   86    192.5-195                                                                             66.31;68.20                              phenyl   (2-PrOH)                                                           31 4-Tolyl 2,6-Di- 2 73 169 68.68/71.30                                         bromo-4-   (2-PrOH)                                                           nitro-                                                                        phenyl                                                                    ______________________________________                                    

EXAMPLE 32

5-Methoxy-1-(toluene-4-sulphonyl)-3-[5-(3-trifluoromethylphenyl)-1,2,4-oxadiazol-3-ylmethoxy]-1H-indazole##STR9##

3.06 g (9.5 mmol) of 5-methoxy-1H-indazol-3-yl toluene-4-sulphonate aredissolved in 50 ml of DMSO and treated in portions with 0.34 g (14.2mmol) of sodium hydride (95 per cent). After stirring for 15 minutes, asolution of 2.5 g (9.5 mmol) of3-chloromethyl-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole in 20 mlof DMSO are added dropwise and the mixture is stirred at 60° C. for 3hours. After cooling, it is stirred into 200 ml of water, stirred for 6hours, and the precipitate is filtered off with suction andrecrystallized from ethanol.

Yield: 1.9 g (36.7% of theory); m.p. 138-144° C.; ¹³ C-M (DMSO-d₆ ; 300MHz): δ=19.0 CH₃ ; 54.1 CH₃ O; 60.0 CH₂ O.

The synthesis of the compounds of Examples 33 to 50 is carried outanalogously to the procedure as in Example 32.

                                      TABLE 2                                     __________________________________________________________________________    3-Benzyloxyindazole-1-sulphonamides or heteroanalogues                                                                     Formula VII                      R.sup.1 = CH.sub.3 O                                                                                                    .sup.13 C-NMR                              (DMSO-d.sub.6)                                                              Yield M.p. CH.sub.2                                                        Example R.sup.2 R.sup.3 (% of theory) [° C.] [ppm]                   __________________________________________________________________________    33   4-Tolyl                                                                             4-Benzyl-          23     159-161                                                                            70.51; 71.52                            oxyphenyl  (MeCN)                                                           34 4-Tolyl 2-Methoxy-5- 15 132-136 65.67                                        acetylphenyl  (EtOH)                                                        35 4-Tolyl 2-Fluoro-6- 21 156-160 61.76                                         chlorophenyl  (2-PrOH)                                                      36 4-Chloro- 2-Fluoro-6- 23 151-155 62.78                                      phenyl chlorophenyl  (EtOH)                                                  37 4-Fluoro- 3-Trifluoro- 10 113 70.48                                         phenyl methylphenyl  (MeOH)                                                  38 4-Tolyl 2-Fluoro- 23 151-152 65.43                                           phenyl  (2-PrOH)                                                            39 4-Fluoro- 2-Fluoro- 18 149-150 66.39                                        phenyl phenyl  (MeCN)                                                        40 4-Fluoro- 4-Fluoro-  9 110-114 69.16                                        phenyl phenyl  (EtOH)                                                        41 4-Tolyl 4-Chloro-2- 25  85-90 67-74                                          nitrophenyl  (2-PrOH)                                                        - 42 4-Tolyl                                                                                                           34 198-202  (MeCN) 68.68;                                                   102.66                                 - 43 4-Tolyl                                                                                                           19 183-184  (EtOAc) 65.35;                                                  65.63; 49                              - 44 4-Tolyl                                                                                                           10 248-252  (MeCN) 65.25;                                                   65.79;  92.38                          - 45 4-Fluoro-  phenyl                                                                                                 10 246-250  (MeCN) 64.55;                                                   65.93; 58                              - 46 4-Tolyl                                                                                                           10 168-174  (EtOH) 62.82                                                      - 47 4-Chloro-  phenyl                                                        14 180-182  (EtOH) 60.92                                                      - 48 4-Tolyl                                                                  41 153-157  (MeCN) 61.27                                                      - 49 4-Tolyl                                                                   5 172-174  (EtOH) 61.34                                                      - 50 4-Tolyl                                                                  23 180-181  (MeCN) 67.77          __________________________________________________________________________

EXAMPLE 516-{2-[5-Methoxy-1-(toluene-4-sulphonyl)-1H-indazol-3-yloxy]acetyl}-3,4-dihydro-1H-quinolin-2-one##STR20##

3.66 g (11.5 mmol) of 5-methoxy-1H-indazol-3-yl toluene-4-sulphonate aredissolved in 50 ml of DMSO and treated in portions with 0.41 g (17.2mmol) of sodium hydride (95 per cent). After stirring for 15 minutes, asolution of 3.16 g (11.5 mmol) of6-bromoacetyl-2-oxo-1,2,3,4-tetrahydroquinoline in 30 ml of DMSO isadded dropwise and the mixture is stirred at 60° C. for 3 hours. Aftercooling, it is stirred into 200 ml of water, stirred for 6 hours, andthe precipitate is filtered off with suction and recrystallized fromacetonitrile.

Yield: 2.2 g (37.8% of theory); M.p. 232-237° C.; ¹³ CNMR (DMSO-d₆ ; 300MHz); δ=21.4 CH₃ ; 23.2 CH₂ ; 28.7 CH₂ ; 56.1 CH₃ O; 69.5 CH₂ O; 189.3 2x C═O. IR (KBr): 1680 C═O.

The synthesis of the compounds of Examples 52 to 65 is carried outanalogously to the procedure as in Example 51.

                                      TABLE 3                                     __________________________________________________________________________    3-Phenacylindazole-1-sulphonamide                                                                                Formula VIII                               R.sup.1 = CH.sub.3 O                                                                                          .sup.13 C-NMR                                      Yield M.p. (DMSO-d.sub.6)                                                  Example R.sup.2 R.sup.3 (% of theory) [° C.] CH.sub.2 O/C═O      __________________________________________________________________________    52   4-Tolyl                                                                              4-Chloro-                                                                             7     173-180                                                                             70.00/190.55                                      phenyl  (MeCN)                                                              53 4-Methoxy- 4-Chloro- 37 183-183.5 70.59/191.38                              phenyl phenyl  (MeCN)                                                        54 4-Chloro- 4-Chloro- 21 166-169 72.50/192.84                                 phenyl phenyl  (2-PrOH)                                                      55 4-Tolyl 3,4-Di-  9 173-178 72.65/192.52                                      chloro-  (MeCN)                                                               phenyl                                                                      56 4-Chloro- 3,4-Di- 13 175-178 70.42/190.03                                   phenyl chloro-  (MeCN)                                                         phenyl                                                                      57 4-Acetyl- 3,4-Di-  4 225-229 71.51/191.47                                   amino- chloro-  (EtOH)                                                        phenyl phenyl                                                                58 Naphthalen- 3,4-Di- 17 210-212 70.97/190.68                                 1-yl chloro-  (MeCN)                                                           phenyl                                                                      59 Quinolin- 3,4-Di- 33 213-218 71.19/191.43                                   8-yl chloro-  (MeCN)                                                           phenyl                                                                      60 4-Tolyl 4-Diphenyl  8 196-200 73.54/194.35                                     (MeCN)                                                                    61 4-Chloro- 4-Diphenyl 44 207-210 73.04/193.65                                phenyl   (MeCN)                                                              62 4-Methoxy- 4-Diphenyl 23 198-205 71.55/192.43                               phenyl   (MeCN)                                                              63 4-Acetyl- 4-Diphenyl  2 248-249 71.53/192.47                                amino-   (n-BuOH)                                                             phenyl                                                                     __________________________________________________________________________

Starting from 5-nitro-1H-indazol-3-yl toluene-4-sulphonate, thefollowing derivatives were prepared analogously:

    ______________________________________                                        Formula VIII, R.sup.1 = NO.sub.2                                                                         Yield         .sup.13 C-NMR                          Ex-   (% of M.p. (DMSO-d.sub.6)                                               ample R.sup.2 R.sup.3 theory) [° C.] CH.sub.2 O/C═O              ______________________________________                                        64     4-Tolyl 4-Chloro- 35    201-207 72.06/191.74                               phenyl  (MeOH)                                                            ______________________________________                                    

By reduction of the 5-nitro group corresponding to the procedure as inExample 87, the following derivatives were prepared:

    ______________________________________                                        Formula VIII, R.sup.1 = NH.sub.2                                                                         Yield         .sup.13 C-NMR                          Ex-   (% of M.p. (DMSO-d.sub.6)                                               ample R.sup.2 R.sup.3 theory) [° C.] CH.sub.2 O/C═O              ______________________________________                                        65     4-Tolyl 4-Chloro- 64    193-195.5                                                                             71.28/192.18                               phenyl  (2-PrOH)                                                          ______________________________________                                    

EXAMPLE 66N-(2,4-Difluorophenyl)-2-[5-methoxy-1-(toluene-4-sulphonyl)-1H-indazol-3-yloxy]acetamide##STR22##

3.66 g (11.5 mmol) of 5-methoxy-1H-indazol-3-yl toluene-4-sulphonate aredissolved in 50 ml of DMSO and treated in portions with 0.41 g (17.2mmol) of sodium hydride (95 per cent). After stirring for 15 minutes, asolution of 2.36 g (11.5 mmol) of α-chloro-2,4-difluoroacetanilide in 20ml of DMSO is added dropwise and the mixture is stirred at 60° C. for 3hours. After cooling, it is stirred into 200 ml of water, stirred for 6hours, and the precipitate is filtered off with suction andrecrystallized from methanol. The recrystallized precipitate is filteredoff with suction (by-product), the filtrate is concentrated to 30 mland, after crystallization is complete, the product is filtered off withsuction.

Yield: 1.0 g (17.8% of theory); m.p. 155-159° C.; ¹³ C-NMR (DMSO-d₆ ;300 MHz): δ=20.8 CH₃ ; 55.7 CH₃ O; 67.2 CH₂ O; 165.4 C═O. IR (KBr): 1706C═O.

The synthesis of the compounds of Examples 67 to 76 is carried outanalogously to the procedure as in Example 66.

                                      TABLE 4                                     __________________________________________________________________________    Other 3-subst. indazol-1-sulphonamides                                                                                   Formula IX                         R.sup.1 = CH.sub.3 O                                                                                                   .sup.13 C-NMR                               (DMSO-d.sub.6)                                                              Yield M.p. CH.sub.2 O                                                      Example R.sup.2 R.sup.3 (% of theory) [° C.] [ppm]                   __________________________________________________________________________      67 4-Tolyl                                                                                                             16 128##                                                                    -129  (2-PrOH) 70.13                    - 68 4-Tolyl                                                                                                           5 135-140  (EtOH) 72.79                                                      - 69 4-Tolyl                                                                  18 142-144  (EtOH) 67.08                                                      - 70 4-Fluoro-  phenyl                                                         6 154-157  (MeCN) 69.58                                                      - 71 4-Tolyl                                                                   5 165-169  (MeOH) 69.40                                                      - 72 4-Tolyl                                                                  29 177-178.5  (EtOH) 67.97                                                    - 73 4-Tolyl                                                                  39 196-200  (MeCN) 67.79                                                      - 74 4-Tolyl                                                                  24 147-151  (EtOH) 65.86                                                      - 75 4-Tolyl                                                                  14 238-241  (MeCN) 67.20                                                      - 76 4-Methoxy-  phenyl                                                       24 216 dec.  (MeCN) 66.85          __________________________________________________________________________

EXAMPLE 77 3-(6-Chlorobenzo[1,3]dioxol-5-ylmethoxy)-5-methoxy-1(3-nitrobenzyl)-1H-indazole ##STR34##

4.5 g (15 mmol) of 5-methoxy-1-(3-nitrobenzyl)-1H-indazol-3-ol aredissolved in 100 ml of DMSO and treated in portions with 0.72 g (18mrnol) of sodium hydride (60 per cent). After stirring for 2 hours, asolution of 3.1 g (15 mmol) of 6-chloropiperonyl chloride in 20 ml ofDMSO is added dropwise and the mixture is stirred at 60° C. for 3 hours.After cooling, 250 ml of water are added dropwise, the mixture isstirred for 4 hours and the solid is filtered off with suction. Theprecipitate is first recrystallized from isopropanol, then from ethanol.

Yield: 3.3 g (47.0% of theory); m.p. 134-135.5° C.; ¹³ C-NMR (DMSO-d₆ ;300 MHz): δ=51.5 CH₂ N; 55.7 CH₃ O; 67.8 CH₂ O; 101.7 OCH₂ O.

The synthesis of the compounds of Examples 78 to 85 is carried outanalogously to the procedure as in Example 77.

                                      TABLE 5                                     __________________________________________________________________________    1-(3-Nitrobenzyl)-3-alkyloxyindazoles                                                                             Formula XI                                                                .sup.13 C-NMR                                     Yield M.p. (DMSO-d.sub.6)                                                   Example R (% of theory) [° C.] N--CH.sub.2 /O--CH.sub.2              __________________________________________________________________________    78   4-Chlorophenoxyethyl                                                                         31     118-120                                                                            51.46/66.68;                                       (2-PrOH) 67.32                                                             79 4-Nitrophenoxyethyl 75 163-166 50.48/67.03;                                   (acetone) 67.10                                                            80 4-Carboxaminophenoxy- 94 159-162 50.47/66.22;                               ethyl  (EtOH) 67.28                                                          81 2-Bromo-4,6- 44  63-73 52.01/68.32;                                         difluorophenoxyethyl  (2-PrOH) 72.80                                         82 2,6-Dibromo-4- 18 118-121 51.95/68.09;                                      nitrophenoxyethyl  (EtOAc) 72.59                                              - 83                                                                                                         55 160-170  (acetone) 50.39/68.30                                             - 84 2,6-Dichlorobenzyl 61 139-143                                          50.49/65.31                                        (EtOH)                                                                      - 85                                                                                                         53 141-144  (2-PrOH) 51.91/71.00            __________________________________________________________________________

EXAMPLE 863-[3-(4-Fluorophenyl)propoxy]-5-nitro-1-(3-nitrobenzyl)-1H-indazole##STR38##

5.97 g (19 mmol) of 5-nitro-1-(3-nitrobenzyl)-1H-indazol-3-ol and 4.47 g(29 mmol) of 3-(4-fluorophenyl)propan-1-ol are dissolved in 150 ml oftetrahydrofuran and treated with 7.6 g (29 mmol) of triphenylphosphine.A solution of 5.1 g (29 mmol) of diethyl azodicarboxylate in 10 ml oftetrahydrofuran is then added dropwise and the mixture is stirred at 20to 25° C. for 5 hours. It is then distilled to dryness in vacuo, theresidue is stirred with 50 ml of 1N sodium hydroxide solution for 2hours and neutralized with 5 ml of 10N hydrochloric acid, and theaqueous supernatant is decanted. The oily product is crystallized bystirring with methanol and recrystallized from n-butanol.

Yield: 4.7 g (54.9% of theory); m.p. 85-90° C.; ¹³ C-NMR (DMSO-d₆ ; 300MHz); δ=30.35 CH₂ ; 30.91 CH₂ ; 51.15 CH₂ N; 68.95 CH₂ O.

EXAMPLE 873-[3-(6-Chlorobenzo[1,3]dioxol-5-ylmethoxy)-5-methoxyindazol-1-ylmethyl]phenylamine##STR39##

2.2 g (4.7 mmol) of3-(6-chlorobenzo[1,3]dioxol-5-yl-methoxy)-5-methoxy-1-(3-nitrobenzyl)-1H-indazoleare dissolved in 500 ml of dioxane, treated with about 1 g of Raneynickel and hydrogenated for 2 hours at 70° C., 20 bar. After cooling,the catalyst is filtered off with suction, the filtrate is distilled todryness in vacuo and the residue is recrystallized from dioxane.

Yield: 1.8 g (87.5% of theory); m.p. 153-154° C.; ¹³ C-NMR (DMSO-d₆ ;300 MHz): δ=52.6 CH₂ N; 55.7 CH₃ O; 67.9 CH₂ O; 101.7 OCH₂ O.

The synthesis of the compounds of Examples 88 to 90 is carried outanalogously to the procedure as in Example 87.

                                      TABLE 6                                     __________________________________________________________________________    1-(3-Aminobenzyl)-3-alkyloxyindazoles                                                                                Formula XII                                                               .sup.13 C-NMR                                  Yield M.p. (DMSO-d.sub.6)                                                   Example R (% of theory) [° C.] N--CH.sub.2 /O--CH.sub.2              __________________________________________________________________________      88                                                                                                               89 227##                                                                    -230  (2-PrOH) 50.99/66.63;  67.35                                              - 89                                                                          77 176-178  (dioxane) 52.00/66.43;                                          67.33                                         - 90                                                                                                            40 155-158  (2-PrOH) 50.84/70.57         __________________________________________________________________________

EXAMPLE 911-(4-Fluorobenzyl)-5-methoxy-3-[2-(4-nitrophenoxy)ethoxy]-1H-indazole##STR44##

4.1 g (15 mmol) of 1-(4-fluorobenzyl)-5-methoxy-1H-indazol-3-ol aredissolved in 100 ml of DMSO and treated in portions with 1 g (25 mmol)of sodium hydride (60 per cent) . After stirring for 2 hours, a solutionof 3.7 g (15 mmol) of 2-(4-nitrophenoxy)ethyl bromide in 20 ml of DMSOis added dropwise and the mixture is stirred at 80-90° C. for 3 hours.After cooling, 250 ml of water are added dropwise, the mixture isstirred for 4 hours, and the solid is filtered off with suction andrecrystallized from ethanol.

Yield: 3.1 g (47.2% of theory); m.p. 117-120.5° C.; ¹³ C-NMR (DMSQ-d₆ ;300 MHz): δ=50.7 CH₂ N; 55. 4 CH₃ O; 67.0 CH₂ O; 67.2 CH₂ O.

The synthesis of the compounds of Examples 92 to 98 is carried outanalogously to the procedure as in Example 91.

                                      TABLE 7                                     __________________________________________________________________________    1-(4-Fluorobenzyl)-3-alkoxyindazoles                                                                                  Formula XIII                                                              .sup.13 C-NMR                                 Yield M.p. (DMSO-d.sub.6)                                                   Example R (% of theory) [° C.] N--CH.sub.2 /O--CH.sub.2              __________________________________________________________________________      92                                                                                                                48 R46##                                                                     81.5-83.5  (EtOH) 50.51/65.49;                                               65.99                                        - 93                                                                                                             75 190-195  (2-PrOH) 50.73/66.52;                                           67.21                                        - 94                                                                                                             40  64-66  (2-PrOH) 52.22/68.27;                                            72.93                                        - 95                                                                                                             84  97-98  (EtOH) 52.25/60.10                                                 - 96                                                                          73  72-75  (EtOH) 51.96/58.57                                                 - 97                                                                          75 135-136.5  (2-PrOH) 52.31/68.32                                            - 98                                                                          73 119-121  (EtOH) 53.79/72.73          __________________________________________________________________________

EXAMPLE 993-[2-(2-Bromo-4,6-difluorophenoxy)ethoxy]-5-methoxy-1-[2-(4-nitrophenoxy)ethyl]-1H-indazole##STR53##

2.7 g (8 mmol) of 5-methoxy-1-[2-(4-nitrophenoxy)ethyl]-1H-indazol-3-olare dissolved in 50 ml of DMSO and treated in portions with 0. 4 g (16.7mmnol) of sodium hydride (95 per cent). After stirring for 15 minutes, asolution of 2.17 g (8 mmol) of1-(2-bromo-4,6-difluorophenoxy)-2-chloroethane in 20 ml of DMSO is addeddropwise and the mixture is stirred at 60° C. for 3 hours. Aftercooling, 200 ml of water are added, the mixture is stirred for 6 hours,and the solid is filtered off with suction and recrystallized fromethanol.

Yield: 1.7 g (37.6% of theory); m.p. 102° C.; ¹³ C-NMR (DMSQ-d₆ ; 300MHz): δ=46.3 CH₂ N; 54.3 CH₃ O; 66.6 CH₂ O; 66.9 0H₂ O; 71.3 CH₂ O.

The synthesis of the compounds of Examples 100 to 111 is carried outanalogously to the procedure as in Example 99.

                                      TABLE 8                                     __________________________________________________________________________    1-(Phenoxyethyl)-3-alkyloxyindazoles                                                                             Formula XIV                                R.sup.2 = NO.sub.2                                                                                              .sup.13 C-NMR                                   Yield M.p. (DMSO-d.sub.6)                                                   Example R.sup.1 (% of theory) [° C.] OCH.sub.2                       __________________________________________________________________________      100                                                                                                             48 110##                                                                    -116  (EtOH) 67.86; 68.55;  68.84                                               - 101                                                                         18 157-161  (EtOAc) 65.90; 66.06;                                           70.53                                          - 102                                                                                                          33 181-184  (MeCN) 68.21; 71.36                                               - 103                                                                         29 195-197  (MeCN) 66.91; 70.44                                               - 104                                                                         63 153-156  (MeCN) 67.71; 70.89                                               - 105                                                                         50 158-165  (MeCN) 67.78; 70.60                                               - 106                                                                         40 167-171  (MeCN) 67.51; 67.03                                               - 107                                                                         55  91-98  (EtOH) 64.69; 66.97                                                - 108                                                                         47  91-96  (EtOH) 67.87; 69.65                                                - 109                                                                         60 144-147  (MeCN) 64.50; 67.89                                               - 110                                                                         53 177-178.5  (MeCN) 63.93; 64.82;                                          67.04; 90.63                                __________________________________________________________________________

    __________________________________________________________________________    Formula XIV                                                                     R.sup.2 = Cl                                                                                                 .sup.13 C-NMR                                    Yield M.p. (DMSO-d.sub.6)                                                   Example R.sup.1 (% of theory) [° C.] OCH.sub.2                       __________________________________________________________________________      111                                                                                                            6 1106##                                                                    -116  (EtOH) 66.92; 67.32;  67.60            __________________________________________________________________________

EXAMPLE 1123-[2-(2-Bromo-4,6-difluorophenoxy)ethoxy]-1-[3,4-dichlorobenzyl]-5-methylthio-1H-indazole##STR67##

3.6 g (11 mmol) of 1-(3,4-dichlorobenzyl)-5-methylthio-1H-indazol-3-olare dissolved in 100 ml of DMSO and treazed in portions with 0.34 g(13.2 mmol) of sodium hydride (95 per cent). After stirring for 2 hours,a solu:ion of 3.0 g (11 mmol) of1-(2-bromo-4,6-difluorophenoxy)-2-chloroethane in 20 ml of DMSO is addeddropwise and the mixture is stirred at 60° C. for 3 hours. Aftercooling, 200 ml of water are added dropwise, the mixture is extractedthree times with 100 ml of ethyl acetate each time, and the combinedorganic phases are washed with 50 ml of water, dried over sodiumsulphate and distilled to dryness in vacuo. The residue is dissolved in100 ml of chloroform, extracted by shaking with 100 ml each of 1N sodiumhydroxide solution and 100 ml of water, the organic phase is dried oversodium sulphate and distilled to dryness, and the residue is purified bymeans of liquid chromatography (silica gel 60/0.2-0.5 mm, eluentmethylene chloride/methanol=9/1).

Yield: 0.3 g (5% of theory); m.p. 46-49° C.; ¹³ C-NMR (DMSO-d₆ ; 300MHz); δ=18. 4 CH₃ S; 51.7 CH₂ N; 68.3 CH₂ O; 72.7 CH₂ O.

The synthesis of the compound of Example 113 is carried out analogouslyto the procedure as in Example 112.

                                      TABLE 9                                     __________________________________________________________________________    Subst. 1-benzyl-3-alkyloxy-5-methylthioindazoles                                                                Formula XIV                                                                .sup.13 C-NMR                                      Yield M.p. (DMSO-d.sub.6)                                                   Example R (% of theory) [° C.] N--CH.sub.2 /O--CH.sub.2              __________________________________________________________________________      113                                                                                                          74 134##                                                                    -139  (EtOH) 51.62/71.09                       __________________________________________________________________________

EXAMPLE 1141-{1-(2,4-Dichlorobenzyl)-3-[2-(4-nitrophenoxy)ethoxy]-1H-indazol-5-yl}-3-naphthalen-1-ylurea##STR70##

2.9 g (6.1 mmol) of1-[1-(2,4-dichlorobenzyl)-3-hydroxy-1H-indazol-5-yl]-3-naphthalen-1-ylureaare dissolved in 70 ml of DMSO and treated in portions with 0.22 g (9mmol) of sodium hydride (95 per cent). After stirring for 10 minutes, asolution of 1.5 g (6.1 mmol) of 2-(4-nitrophenoxy)ethyl bromide in 10 mlof DMSO is added dropwise and the mixture is stirred at 60° C. for 3hours. After cooling, 400 ml of water are added, and the mixture isstirred for 3 hours and extracted three times with 400 ml of ethylacetate. The combined organic phases are washed with 100 ml of water,dried over sodium sulphate, distilled to dryness in vacuo and theresidue is recrystallized from methanol.

Yield: 1.3 g (33.2% of theory); m.p. 179-183° C.; ¹³ C-NMR (DMSO-d₆ ;300 MHz): δ=48.8 CH₂ N; 67.1 CH₂ O; 67.3 CH₂ O.

The synthesis of the compounds of Examples 115 to 123 us carried outanalogously to the procedure as in Example 114.

                                      TABLE 10                                    __________________________________________________________________________    Subst. 1-benzyl-3-alkyloxyindazol-5-amines                                      #STR71##                                                                       - R.sup.2 = 3,4-Cl.sub.2                                                                                           Yield         .sup.13 C-NMR                                                                     (% of  M.p.                                                               (DMSO-d.sub.6)                                                                 Example R.sub.1                                                              R.sub.3 theory)                                                               [° C.]                                                                 N--CH.sub.2                                                                   /O--CH.sub.2            __________________________________________________________________________      115                                                                                                                                 #STR72##                                                                      19 159##                                                                    -168  (MeOH)                                                                  48.33/64.65;  65.35        - 116                                                                                                                              #STR74##                                                                       6 178-188                                                                  (MeOH) 48.37/65.29;                                                            65.48                     - 117                                                                                                                              #STR76##                                                                      23 146-153                                                                  (MeOH) 50.63/71.05                                                              - 118                                                                         #STR78##                                                                      23 149-155                                                                  (MeOH) 50.44/71.01                                                              - 119                                                                         #STR80##                                                                      50 209-211                                                                  (BuOH) 50.71/71.03      __________________________________________________________________________

    __________________________________________________________________________    Formula XVI                                                                     R.sup.2 = 2,4-Cl.sub.2                                                                                                             .sup.13 C-NMR                                                                     Yield M.p.                                                                (DMSO-d.sub.6)                                                                 Example R.sub.1                                                              R.sub.3 (% of                                                                 theory) [°                                                             C.] N--CH.sub.2                                                               /O--CH.sub.2           __________________________________________________________________________      120                                                                                                                                  #STR82##                                                                      31 184##                                                                    -187  (dioxane)                                                               49.13/66.93;                                                                  67.82                     - 121                                                                                                                               #STR84##                                                                      33  179-183                                                                 (MeOH) 48.87/67.16;                                                             67.33                   - 122                                                                                                                               #STR86##                                                                      26 185-187                                                                  (BuOH) 49.00/71.01        - 123                                                                                                                               #STR88##                                                                      39 192-196                                                                  (MeCN) 48.98/70.98     __________________________________________________________________________

To determine the anti-asthmatic, anti-allergic, anti-inflammatory and/orimmunomodulating properties of the compounds according to the invention,in-vitro and in-vivo investigations were carried out. The compoundsaccording to the invention as in formula I are surprisinglydistinguished by immunophilin binding and inhibit its peptidyl-prolylcis-transisomerase (PPIase) activity. For the initial screening (10μmol/l), the inhibition of human cyclophilin B in the PPIase test isdetermined.

Assay for the Determination of the Peptidylprolyl Isomerase (PPIase)Activity and Inhibition

Method:

The PPIase activity is tested according to a globally customary enzymetest: G. Fischer, H. Bang, C. Mech, Biomed. Biochim. Acta 43 1101-1111;G. Fischer, H. Bang, A. Schellenberger, Biochim. Biophys. Acta 791(1984), 87-97; D. H. Rich et al., J. Med. Chem. 38 (1995), 4164-4170.

The compounds of the general formula I according to the invention arepreincubated at 4° C. for 15 minutes together with 10 nmol of Cyp B. Theenzyme reaction is started using the test peptideSuc-Ala-Ala-Pro-Phe-Nan after addition of chymotrypsin and HEPES buffer.The extinction change at 390 nm is then monitored and evaluated. Thephotometrically determined extinction change results from twosub-reactions: a) the rapid chymotryptic cleavage of the trans-peptide;b) the non-enzymatic cis-trans isomerization, which is catalysed bycyclophilins. The corresponding PPIase activities of the compounds ofthe general formula I according to the invention are shown in Table 11:

                  TABLE 11                                                        ______________________________________                                                    Inhibition of the PPIase                                            Example activity in [%] at 10 μM                                         ______________________________________                                         1          95                                                                   7 70                                                                          9 90                                                                         32 70                                                                         41 71                                                                         66 40                                                                         73 67                                                                         84 90                                                                         114  100                                                                      116  90                                                                       121  100                                                                    ______________________________________                                    

Inhibition of Late-phase Eosinophilia 24 h After Inhalational OvalbuminChallenge in Actively Sensitized Guinea-pigs

Method:

The inhibition of pulmonary eosinophil infiltration by the substances istested in an in-vivo test on male Dunkin-Hartley guinea-pigs (200-250 g)sensitized against ovalbumin (OVA). The sensitization is carried out bymeans of two intraperitoneal injections of a suspension of 20 μg of OVAtogether with 20 mg of aluminium hydroxide as an adjuvant in 0.5 ml ofphysiological saline solution per animal on two successive days. 14 daysafter the second injection, the animals are pretreated with mepyraminemaleate (10 mg/kg i.p.) in order to protect them from anaphylacticdeath. 30 minutes later, the animals are exposed for 30 sec in a plasticbox to an OVA aerosol (0.5 mg/ml) which is generated by a nebulizerdriven by compressed air (19.6 kPa) (allergen challenge). Controlanimals are nebulized with physiological saline solution. 24 hours afterthe challenge, the animals are anaesthetized with an overdose ofethylurethane (1.5 g/kg of body weight i.p.) and a bronchoalveolarlavage (BAL) is carried out with 2×5 ml of physiological salinesolution. The BAL fluid is collected, centrifuged at 300 rpm for 10 minand the cell pellet is then resuspended in 1 ml of physiological salinesolution. The eosinophils are stained using the Becton-Dickinson testkit (N. 5877) for eosinophils and counted in a Neubauer chamber. 2control groups (nebulization with physiological saline solution andnebulization with OVA solution) are additionally included in each test.

The percentage inhibition of the eosinophilia of the test group treatedwith substance is calculated according to the following formula:

    (A-C)-(B-C)/(A-C)×100=% inhibition

The test substances are administered intraperitoneally or orally as asuspension in 10% polyethylene glycol 300 and 0.5% strength5-hydroxyethylcellulose 2 hours before allergen challenge. The controlgroups are treated with the vehicle according to the administration formof the test substance. The number of animals per control and test groupis 3-10. The results are listed in the following table:

                                      TABLE 12                                    __________________________________________________________________________                       Eosinophil                                                     million/animal                                                              Dose  x ± s Inhibition                                                   Example                                                                             [mg/kg]                                                                            Administration                                                                        A      B      C      [%]                                   __________________________________________________________________________     1    10   i.p. -2 h                                                                             2.11 ± 1.05                                                                       1.23 ± 0.38                                                                       0.67 ± 0.23                                                                       61                                       30 p.o. -2 h 3.49 ± 1.47 1.75 ± 1.86 0.83 ± 0.30 65                  8 10 i.p. -2 h 2.46 ± 1.08 1.84 ± 0.94 0.97 ± 0.47 41                                                      32 10 i.p. -2 h 1.93 ± 0.75                                               0.86 ± 0.49 0.66 ± 0.12 85                                               91 10 i.p. -2 h 2.89 ± 1.66                                               1.16 ± 0.65 0.47 ± 0.24 71                                               99 10 i.p. -2 h 1.93 ± 0.75                                               1.35 ± 0.67 0.66 ± 0.12 46                                                30 p.o. -2 h 1.81 ± 0.23                                                 1.33 ± 0.23 0.33 ± 0.08 33                                               107  10 i.p. -2 h 2.46 ± 1.08                                             1.44 ± 0.92 0.97 ± 0.47 68                                               114  10 i.p. -2 h 1.93 ± 0.75                                             1.19 ± 0.43 0.66 ± 0.12         __________________________________________________________________________                                            58                                     A = Eosinophils in the control group with OVA challenge and vehicle           B = Eosinophils in the group treated with substance with OVA challenge        C = Eosinophils in the control group with 0.9% strength NaCl challenge an     vehicle                                                                       x = Average value                                                             s = Standard deviation                                                   

The compounds according to the invention are thus particularly suitablefor the production of medicaments for the treatment of diseases whichare connected with the suppression of immunological processes.

What is claimed is:
 1. 1,5- and 3-O-substituted 1H-indazoles of formula(I) ##STR90## wherein X is --SO₂ --, --SO--, --(CH₂)_(p) --, --(CH₂)_(p)--O--, --(CH₂)_(p) --(C═O)--, --(CH₂)_(p) --(C═O)--NH--, --(CH₂)_(p)--CHOH--, --CHOH--(CH₂)_(p) --, --(CH₂)_(p) --CH═CH--,--CH═CH--(CH₂)_(p) --,Y is --(CH₂)_(p) --, --(CH₂)_(p) --O--,--(CH₂)_(p) --(C═O)--, --(CH₂)_(p) --(C═O)--NH--, --(CH₂)_(p)--(C═O)--NH--(CH₂)_(p) --, --(CH₂)_(p) --CHOH--, --CHOH--(CH₂)_(p) --,--(CH₂)_(p) --CH═CH--, --CH═CH--(CH₂)_(p) --, Z is --O--, --S--, --SO--,--SO₂ --NH, --O--(CH₂)_(p) --, --NH--(C═O)--, --NH--(C═O)--NH--,--NH--(C═O)--O--, --NH--CH₂ --(C═O)-- and --NH--(C═O)--CH₂ --, P is acardinal number from 1 to 4, R¹, R² and R³ are the same or different,and are mono-, bi- or tricyclic saturated or mono- or polyunsaturatedcarbocycles having from 5 to 14 ring members, or mono-, bi- or tricyclicsaturated or mono- or polyunsaturated heterocycles having from 5 to 15ring members and from 1 to 6 heteroatoms, wherein the carbocycles andthe heterocycles can be mono- or polysubstituted by --C₁₋₆ -alkyl,--O--C₁₋₆ -alkyl, --O--C₃₋₇ -cycloalkyl, mono-, bi- or tricyclicsaturated or mono- or polyunsaturated carbocycles having from 3 to 14ring members, mono-, bi- or tricyclic saturated or mono- orpolyunsaturated heterocycles having from 5 to 15 ring members and from 1to 6 heteroatoms, R¹ can also be H provided that X is not CH₂), and R³--Z can also be NO₂ and their pharmaceutically acceptable salts, butexcluding if Y═--(CH₂)_(p) --(C═O)--, --(CH₂)_(p) --(C═O)--NH--, then R²is not pyridine, piperazine, pyrimidine, tetrahydropyridine; and when Zis --NH--(C═O)--, --NH--(C═O)--NH--, --NH--(C═O)--O--, --NH--(C═O)--CH₂-- and R¹ is at the same time phenyl, monosubstituted or polysubstitutedby --COOH, --COOC₁₋₆ -alkyl, --(CH₂)_(p) --COOH, --(CH₂)_(p) --COOC ₁₋₆-alkyl, --CONHC₁₋₆ -alkyl, --CONHC₆₋₁₄ -aryl, --CONHSO₂ C₁₋₆ -alkyl,--CONHSO₂ C₆₋₁₄ -aryl, 1H-tetrazol-5-yl, then R² must not be phenyl,monosubstituted or polysubstituted by CN, halogen, C₁₋₄ -alkyl, C₁₋₄-alkyloxy, CF₃ ; and if R³ --Z is NO₂, then R¹ --X is not benzyl or4-methoxybenzyl and R² --Y is not benzyl or 2-picolyl at the same time.2. The compounds of claim 1, wherein in R¹, R², and R³ said carbocyclesof 4 to 14 ring members are one or more of phenyl, naphthyl, anthranyl,and fluorenyl residue; and wherein in R¹, R², and R³ said heteroatomsare N, O, or S; and wherein said heteroatoms mono- or polysubstitutingsaid carbo-cycles and said heterocycles are N, O and S, --F, --Cl, --Br,--I, --OH, --SH, --NO₂, --NH₂, --NHC₁₋₆ -alkyl, --N(C₁₋₆ -alkyl)₂,--NHC₆₋₁₄ -aryl, --N(C₆₋₁₄ -aryl)₂, --N(C₁₋₆ -alkyl)--(C₆₋₁₄ -aryl),--NHCOC₁₋₆ -alkyl, --NHCOC₆₋₁₄ -aryl, --CONHC₁₋₆ -alkyl, --CONHC₆₋₁₄-aryl, --CONHSO₂ C₁₋₆ -alkyl, --CONHSO₂ C₆₋₁₄ -aryl, --CN, --(CO)C₁₋₆-alkyl, --(CS)C₁₋₆ -alkyl, --COOH, --COOC₁₋₆ -alkyl, --O--C₆₋₁₄ -aryl,--O--(CO)C₁₋₆ -alkyl, --O--(CO)C₆₋₁₄ -aryl, benzyl, benzyloxy, --S--C₁₋₆-alkyl, --S--C₆₋₁₄ -aryl, --CF₃, --(CH₂)_(p) --COOH, --(CH₂)_(p)--COOC₁₋₆ -alkyl, --SO₂ --C₁₋₆ -alkyl, or --SO₂ --C₆₋₁₄ -aryl.
 3. Thecompounds of claim 1, wherein when R¹, R², and/or R³ is a heterocycle,are independently of each other thiophenyl, pyridinyl, isoxazolyl,benzimicdazolyl, benzo[1,3]dioxolyl, pyrimidinyl, quinolyl,quinazolinyl, morpholinyl, pyrrolydinyl, pyrrolyl,benz[1,2,4]oxadiazolyl, or benzothiazolyl residues.
 4. A compound ofclaim 1,being3-[2-(2-bromo-4,6-difluorophenoxy)ethoxy]-5-methoxy-1-(toluene-4-sulfonyl)-1H-indazole;5-methoxy-1-(toluene-4-sulfonyl)-3-[5-(3-trifluoromethylphenyl)-1,2,4-oxadiazol-3-ylmethoxy]-1H-indazole;6-{2-[5-methoxy-1-(toluene-4-sulfonyl)-1H-indazol-3-yloxy]acetyl}-3,4-dihydro-1H-quinolin-2-one;N-(2,4-ditluorophenyl)-2-[5-methoxy-1-(toluene-4-sulfonyl)-1H-indazol-3-yloxy]acetamide;3-(6-chlorobenzo[1,3]dioxol-5-ylmethoxy)-5-methoxy-1-(3-nitrobenzyl)-1H-indazole;3-[3-(4-fluorophenyl)-propoxy]-5-nitro-1-(3-nitrobenzyl)-1H-indazole;3-[3-(6-chlorobenzo[1,3]dioxol-5-ylmethoxy)-5-methoxy-indazol-1-ylmethyl]phenylamine;1-(4-fluorobenzyl)-5-methoxy-3-[2-(4-nitrophenoxy)ethoxy]-1H-indazole;3-[2-(2-bromo-4,6-difluorophenoxy)ethoxy]-5-methoxy-1-[2-(4-nitrophenoxy)ethyl]-1H-indazole;3-[2-(2-bromo-4,6-difluorophenoxy)ethoxy]-1-[3,4-dichlorobenzyl]-5-methylthio-1H-indazole;or1-{1-(2,4-dichlorobenzyl)-3-[2-(4-nitrophenoxy)ethoxy]-1H-indazol-5-yl}-3-naphthalen-1-ylurea.5. The pharmaceutically acceptable salts of claim 1, obtained by (i)neutralization of the bases with inorganic or organic bases, (ii)neutralization of the acids with inorganic or organic bases, or (iii)quaternization of a teriary amine to give a quaternary ammonium salt. 6.A process for the treatment of diseases mediated by PPIase, whichcomprises administering to a patient in need therefor a pharmaceuticalcomposition containing as active ingredient the compound or salt ofclaim
 1. 7. An immunomodulating, antiinflammatory, antiallergic processwhich comprises administering to a patient in need therefor apharmaceutical composition containing as active ingredient the compoundor salt of claim
 1. 8. A process for preparing a compound of claim 1,which comprises(a) when X is --SO₂ --, or --SO-- by reacting a1H-indazolyl-3-yl sulfonate of formula ##STR91## in the presence of abase and in the optional presence of a diluent to provide a compound offormula (III) ##STR92## where R¹, R³, X and Z have the same meaning, andreacting a 1H-indazol-3-yl sulfonate of formula (II), or a1-sulfonylindazole of formula (III), optionally in the presence of abase, and in the optional presence of a diluent, with a compound of theformula Hal-Y-R², where R¹, R², R³, X, Y and Z have the same meaning,and Hal is a halogen atom to provide a compound of formula (I); or (b)when X is --(CH₂)_(p) --, --(CH₂)_(p) --O--, --(CH₂)_(p) --(C═O)--,--(CH₂)_(p) --(C═O)--NH--, --(CH₂)_(p) --CHOH--, --CHOH--(CH₂)_(p) --,--(CH₂)_(p) --CH═CH--, --CH═CH--(CH₂)_(p) --, by reacting compounds offormula (III), the optional presence of a base, and in the optionalpresence of a diluent, with a compound of the formula Hal-Y-R², whereR¹, R², R³, X, Y and Z have the same meanings, and Hal is a halogenatom, to provide a compound of formula (I); or (c) where the compound offormula (III) is present as the tautomeric form of the compound offormula (IV) ##STR93##
 9. The process of claim 8, wherein in said theoptional base is sodium hydride, and said optional diluent is dimethylsulfoxide.
 10. A pharmaceutical composition containing at least onecompound of claim 1 as active ingredient, together with apharmaceutically acceptable carrier and/or diluent or auxiliary.
 11. Thepharmaceutical composition of claim 10, when it is in the form of acoated or uncoated tablet, capsule, aerosol, powder formulation, patch,solution, ampoule, or suppository.